Primary hyperparathyroidism (PHPT) in the United States is predominantly an asymptomatic disease characterized by mild hypercalcemia and elevated levels of parathyroid hormone (PTH). Over the past 24 years, this research project has defined the current clinical, biochemical, densitometric, and histomorphometric features of PHPT. The project has also led to new insights into mechanisms of bone loss, with particular reference to PTH's actions at cortical and cancellous sites. We have also begun to characterize new phenotypes of PHPT in patients who have the disorder but in whom the serum calcium concentration is normal. Some of these patients already have indications of skeletal or renal involvement. Others, similar to their mildly hypercalcemic counterparts, are asymptomatic. In the renewal period, we propose to study these normocalcemic variants of PHPT as well as to delineate further specific mechanistic elements of hypercalcemic PHPT. We will characterize neurocognitive aspects with verifiable instrumentation including functional magnetic resonance imaging (fMRI) of the brain. State of the art techniques include: novel approaches to the histomorphometric and molecular analysis of bone tissue; high resolution quantitative computed tomography; quantitative back-scattered electron imaging, Fourier Transform Infrared Imaging Spectroscopy; finite element modeling of high resolution non-invasive imaging as well as the bone biopsy, and fMRI. With these cohorts and new technologies, we will define bone quality, bone strength and specific neurocognitive aspects of PHPT to an extent never before accomplished. We will extend these studies further to determine which abnormalities in bone quality are reversible after parathyroid surgery and how the use of an intervention to block the catabolic pathway of PTH may well unmask latent anabolic potential of PTH even in the setting of chronic exposure. The following specific aims will be pursued: 1. to characterize two new cohorts of subjects with PHPT: normocalcemic symptomatic PHPT and normocalcemic asymptomatic PHPT; 2. to define abnormalities of bone quality in PHPT in both the hypercalcemic and normocalcemic variants and, in the hypercalcemic cohort, to determine their reversibility; 3. to determine bone strength in PHPT. By the end of the renewal period, we will have fully characterized the hypercalcemic and normocalcemic variants of PHPT and will have established how these various phenotypes are different from each other at the clinical, biochemical, morphometric, structural and molecular levels. We will have characterized clinical, mechanistic, biomechanical, and neurocognitive elements of this disease in its classical presentation and in its more recently recognized variants. The results of these studies will enhance our understanding of PHPT and also be highly relevant to clinical management of this common metabolic bone disease. PUBLIC HEALTH RELEVANCE: Primary hyperparathyroidism, a disorder of excess parathyroid hormone secretion, is one of the most common metabolic bone diseases. The project is designed to elucidate aspects of this disorder that have been elusive, but which when characterized, will enhance our approach to the therapy of this disorder.